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Endocrine Reviews, doi:10.1210/er.2002-0050
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Endocrine Reviews 26 (4): 525-582
Copyright © 2005 by The Endocrine Society

Molecular Biology of the 3ß-Hydroxysteroid Dehydrogenase/{Delta}5-{Delta}4 Isomerase Gene Family

Jacques Simard, Marie-Louise Ricketts, Sébastien Gingras, Penny Soucy, F. Alex Feltus and Michael H. Melner

Canada Research Chair in Oncogenetics (J.S., M.-L.R., S.G., P.S.), Oncology and Molecular Endocrinology Research Center, Laval University Medical Center, and Laval University, Quebec, Canada G1V 4G2; and Departments of Obstetrics/Gynecology and Cell Biology (F.A.F., M.H.M.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Correspondence: Address all correspondence and requests for reprints to: Professor Jacques Simard, Cancer Genomics Laboratory, T3-57, Laval University Medical Center (CHUL) Research Center, 2705 Laurier Boulevard, Québec City, Québec, Canada G1V 4G2. E-mail: jacques.simard{at}crchul.ulaval.ca

The 3ß-hydroxysteroid dehydrogenase/{Delta}5-{Delta}4 isomerase (3ß-HSD) isoenzymes are responsible for the oxidation and isomerization of {Delta}5-3ß-hydroxysteroid precursors into {Delta}4-ketosteroids, thus catalyzing an essential step in the formation of all classes of active steroid hormones. In humans, expression of the type I isoenzyme accounts for the 3ß-HSD activity found in placenta and peripheral tissues, whereas the type II 3ß-HSD isoenzyme is predominantly expressed in the adrenal gland, ovary, and testis, and its deficiency is responsible for a rare form of congenital adrenal hyperplasia. Phylogeny analyses of the 3ß-HSD gene family strongly suggest that the need for different 3ß-HSD genes occurred very late in mammals, with subsequent evolution in a similar manner in other lineages. Therefore, to a large extent, the 3ß-HSD gene family should have evolved to facilitate differential patterns of tissue- and cell-specific expression and regulation involving multiple signal transduction pathways, which are activated by several growth factors, steroids, and cytokines. Recent studies indicate that HSD3B2 gene regulation involves the orphan nuclear receptors steroidogenic factor-1 and dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome gene 1 (DAX-1). Other findings suggest a potential regulatory role for STAT5 and STAT6 in transcriptional activation of HSD3B2 promoter. It was shown that epidermal growth factor (EGF) requires intact STAT5; on the other hand IL-4 induces HSD3B1 gene expression, along with IL-13, through STAT 6 activation. However, evidence suggests that multiple signal transduction pathways are involved in IL-4 mediated HSD3B1 gene expression. Indeed, a better understanding of the transcriptional factors responsible for the fine control of 3ß-HSD gene expression may provide insight into mechanisms involved in the functional cooperation between STATs and nuclear receptors as well as their potential interaction with other signaling transduction pathways such as GATA proteins. Finally, the elucidation of the molecular basis of 3ß-HSD deficiency has highlighted the fact that mutations in the HSD3B2 gene can result in a wide spectrum of molecular repercussions, which are associated with the different phenotypic manifestations of classical 3ß-HSD deficiency and also provide valuable information concerning the structure-function relationships of the 3ß-HSD superfamily. Furthermore, several recent studies using type I and type II purified enzymes have elegantly further characterized structure-function relationships responsible for kinetic differences and coenzyme specificity.




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